Keywords

Introduction

The worldwide prevalence of obesity has markedly increased (nearly tripled in 40 years) (Flegal et al. 2013; Wilson et al. 2002; WHO 2020), and it is predicted that the condition will cost the U.S. healthcare system $48–$66 billion a year by 2030 (Wang et al. 2011). To combat the cardiometabolic comorbidities of obesity and their economic burden, global strategies for obesity prevention and treatment are required.

Lifestyle Interventions

Lifestyle initiatives targeting energy intake and physical activity are generally the first approach to weight reduction (Bray et al. 2016). They can trigger a 5–8% reduction in body weight (Heymsfield and Wadden 2017). However, obese persons often lack the motivation to continue with lifestyle management for weight reduction, because obesity is usually asymptomatic. Therefore, long-term weight management in obese persons remains a difficult task, and weight regain is a common problem following weight loss intervention (Heymsfield and Wadden 2017).

Pharmacological Management

The following prescription agents are approved by the U.S. Food and Drug Administration: phentermine (sympathomimetic amine), orlistat (lipase inhibitor), phentermine–topiramate (sympathomimetic amine and an antiepileptic drug), lorcaserin (5-HT2c receptor agonist), naltrexone–bupropion (opioid antagonist and aminoketone antidepressant), and liraglutide (glucagon-like peptide-1 [GLP1] receptor agonist). Yet relatively few patients receive sustained pharmacologic therapy for reasons that encompass insufficient weight loss, side effects, and prompt recurrence of obesity after treatment be interrupted (Heymsfield and Wadden 2017).

The Role of Vaccines

A therapeutic vaccine may be a potential candidate for improving treatment adherence. In general, a vaccine has prolonged therapeutic effects and low frequency of administration, when it succeeds in inducing neutralizing antibodies against a target molecule (Table 22.1).

Table 22.1 Potential vaccines targeting obesity
Full size table

Features of Therapeutic Vaccines

Therapeutic vaccines for the treatment of chronic diseases have the potential to increase treatment adherence, reduce healthcare costs, and offer enhanced specificity for target molecules. When administration of a therapeutic vaccine successfully induces antibodies that bind to the target self-molecule and inhibit its function, the vaccine should have a long-term therapeutic effect. In the case of hypertension vaccines, three doses of a peptide vaccine targeting angiotensin II type 1 receptor reduced blood pressures for 24 weeks after final immunization in hypertensive rats (Azegami et al. 2012), and a DNA vaccine targeting angiotensin II decreased blood pressure for at least 6 months in rats (Koriyama et al. 2015). The prolonged therapeutic effects of such vaccines will mean a low frequency of administration and may result in increased treatment adherence and savings in medication costs.

In addition to their prolonged effect, therapeutic vaccines have the potential to have greater specificity to target molecules compared with conventional low-molecular-weight drugs (Hansel et al. 2010). In general, high specificity to the target tends to result in few off-target effects and low rates of drug–drug interaction, and it may reduce the incidence of side effects (Hansel et al. 2010). Therapeutic vaccines also have some advantages over monoclonal antibody therapy, including lower production costs, no possibility of inducing anti-drug antibodies, and less frequent dosing (Hansel et al. 2010).

Ghrelin Vaccines

The especial feature of the ghrelin peptide is the O-acylation at the Ser3 residue. It uniquely stimulates food ingestion with diminished energy expenditure (Kojima et al. 1999; Nakazato et al. 2001; Tschop et al. 2000; Wortley et al. 2004). Peripheral ghrelin, which is produced mainly in the gastric X/A-like cells, modulates the nucleus tractus solitarius via the vagus nerve. This results in an increase in noradrenaline in the arcuate nucleus of the hypothalamus and consequent appetite stimulation (Date et al. 2006). O-acylation at Ser3 with octanoate, which is mediated by ghrelin O-acyltransferase (GOAT), provides the orexigenic action of ghrelin (Yang et al. 2008); unacylated ghrelin negatively impacts appetite and body weight (Asakawa et al. 2005).

Laboratory experiments demonstrate that antagonization of ghrelin ameliorates obesity. Genetic deletion of ghrelin increases energy expenditure and locomotor activity in mice, which are less prone to diet-induced obesity (Wortley et al. 2005). Genetic deletion of ghrelin receptor (growth-hormone secretagogue receptor: GHSR), GHSR antagonists, and GOAT inhibitors attenuate diet-induced obesity in mice (Zigman et al. 2005; Maletinska et al. 2011; Barnett et al. 2010). However, as of 2019, no anti-obesity drug that targets ghrelin function—such as a ghrelin inhibitor, GHSR antagonist, or GOAT inhibitor—has been clinically available.

Vaccine Against Synthetic Ghrelin Peptides

Zorrilla et al. (2006) synthesized three ghrelin peptides (Ghr1, Ghr2, and Ghr3) for vaccine development in 2006. Keyhole limpet hemocyanin (KLH) and a couple of adjuvants were attached, and antigen-specific antibodies were elicited. Only Ghr1-KLH and Ghr3-KLH induced weight reduction (by 20%) (Zorrilla et al. 2006).

Also in a porcine model, vaccine comprising the N-terminal residues (1–10) of porcine ghrelin, combined with additional molecules, diminished appetite and weight accrual in piglets (Vizcarra et al. 2007).

Virus Like Particles (VLPs)

VLPs are viral proteins that reliably self-assemble and exhibit antigenic epitopes (Kushnir et al. 2012). Clinical trials in other areas have confirmed the concept (Maurer et al. 2005; Ambuhl et al. 2007). Also a ghrelin VLP vaccine was arranged and, in rodents, diminished appetite however not body weight (Andrade et al. 2013). More extensive studies are necessary in the area.

Nanogel-based vaccine

Advances in nanomaterial development have also been applied to the development of innovative anti-obesity vaccines. To avoid the risk of localized skin adverse events and psychological and physiological stress, when vaccines are administered by using injectable delivery methods, nanoparticle drug delivery to mucosal surfaces is an option (Lamichhane et al. 2014). Nanometer-sized polymer hydrogels (nanogels) can incorporate various proteins through hydrophobic interactions and subsequently allow their release in their native form (Azegami et al. 2018). The cationic type of cholesteryl-group-bearing pullulan (cCHP) nanogel is adequate for local application and interaction with nasal dendritic cells (Nochi et al. 2010). A recombinant fusion protein based on mouse ghrelin and PspA (pneumococcal surface protein A), paved the way for an intranasal vaccine using cCHP nanogel. In mice, serum IgG antibodies were elicited and weight gain was reduced (by 7%). Mitochondrial uncoupling protein 1 in brown adipose tissue was upregulated (Azegami et al. 2017).

Glucose-dependent Insulinotropic Polypeptide (GIP) Vaccines

GIP, as one of incretins, promotes pancreatic insulin secretion in a glucose-dependent manner (Sadry and Drucker 2013), and increases adipose tissue (Miyawaki et al. 2002). In animal experiments, a GIP receptor antagonist attenuated diet-induced obesity and subsequently improved glucose metabolism (McClean et al. 2007). GIP combined with bacteriophage Qβ VLPs allowed the development of a vaccine. In a mice model, weight gain was inhibited (by 35%), without hyperglycemia. The anti-obesity response was attributed to elevation of energy expenditure (Fulurija et al. 2008).

Adipocyte Vaccines

A small clinical trial with oral tablets of pig adipose tissue was conducted for 3 months (Bourinbaiar and Jirathitikal 2010). Waist circumference decreased (by 7.6%), however not body weight. In turn, an intraperitoneally injected xenogeneic adipocyte vaccine in rats was followed by adipocyte apoptosis and 50% amelioration of weight increase (Lai et al. 2010).

Somatostatin Vaccine

Pharmacological supplementation with growth hormone (GH) decreases body fat in obese adults (Kim et al. 1999); however, the clinical applications of GH are limited by its very short half-life. Vaccine inhibition of somatostatin, which blocks GH secretion, was attempted by means of intraperitoneal immunization with somatostatin and carrier protein chloramphenicol acetyltransferase. Weight reduction (by 12–13%) and IgG production were achieved (Haffer 2012).

Adenovirus 36 (Ad36) Vaccine

In some large series, many obese persons tested positive for antibodies against Ad36 (Atkinson et al. 2005), and animals respond to Ad36 challenge with increased adiposity (Dhurandhar et al. 2002). An Ad36-based vaccine in mice was successful in preventing body fat elevation (Na and Nam 2014).

Future Possibilities

As therapeutic vaccines elicit the production of antigen-specific antibodies to neutralize biomolecules that promote weight gain, not only ghrelin, GIP, adipocytes, and somatostatin, but also other endogenous molecules can be targeted. The therapeutic vaccine approach is feasible for pathways with which no small-molecule drug has yet been able to interact. Brain and intracellular molecules that cannot be reached by neutralizing antibodies would not be suitable targets. In addition, enhancement of the immune reaction is a trade-off between preferable humoral immune responses and undesired autoimmune reactions.

Better selection of epitope sequences from self-antigens and adjuvants designed to elicit Th2 activity will help to induce Th2-dominant humoral immune responses. Enhanced drug-delivery systems and biotechnology will also help to develop effective and safe vaccines.